1. Field of Invention
This invention realtes to a novel process for the reduction of organic compounds which contain both an amino group and a carboxylic acid group. More particularly, this invention provides a process for the preparation of amino alcohols whereby an organic compound containing both an amino group and a carboxylic acid group is combined with boron trifluoride in a suitable organic liquid medium and this mixture is then treated with diborane, a borane-ether or a borane-organic sulfide complex. After an appropriate interval of time, the reaction mixture is hydrolyzed to yield the corresponding amino alcohol formed by hydrogenation of the carbxylic acid group.
2. Description of the Prior Art
Diborane, B.sub.2 H.sub.6, is an exceedingly powerful, but selective hydrogenating agent for functional groups as disclosed by H. C. Brown in U.S. Pat. No. 2,874,165 and in his book [H. C. Brown, Boranes in Organic Chemistry, Cornell University Press, Ithaca, new York, 1972].
Diborane is a highly reactive gas which rapidly decomposes on exposure to air and moisture. Consequently, it is difficult to handle. Fortunately, diborane is highly soluble in tetrahydrofuran where it exists as a borane-tetrahydrofuran complex which can be represented by the formula: ##SPC1##
Brown has disclosed in U.S. Pat. No. 3,634,277 a convenient method for preparing and stabilizing solutions of this borane-tetrahydrofuran complex in tetrahdyrofuran.
Borane-tetrahydrofuran has been found to be useful for selective hydrogenations and reductions of organic functional groups [H. C. Brown, P. Heim, and N. M. Yoon, J. Amer. Chem. Soc., 92, 1637 (1970)], and this borane complex has been reported to be particularly useful for the selective reduction of carboxylic acids [N. M. Yoon, C. S. Pak, H. C. Brown, S. Krishnamurthy, and T. P. Stocky, J. Org. Chem., 38, 2786 (1973)].
Borane-dimethyl sulfide is a stable, liquid BH.sub.3 complex, and its numerous advantages over the borane-tetrahydrofuran complex have been previously disclosed [L. M. Braun, R. A. Braun, H. R. Crissman, M. Opperman, and R. M. Adams, J. Org. Chem., 36, 2388 (1971)]. The main advantages are that borane-dimethyl sulfide has a molar concentration of borane ten times that of a borane-tetrahydrofuran solution, borane-dimethyl sulfide is soluble in and unreactive toward a wide variety of aprotic solvents, and borane-dimethyl sulfide is apparently stable indefinitely when refrigerated.
Borane-dimethyl sulfide is now commercially available, and its reactivity towards a series of organic functional groups was investigated briefly by Braun and coworkers (supra). Borane-dimethyl sulfide has also been found to be a very useful reagent for the preparation of organoboranes via hydroboration of alkenes [C. F. Lane, J. Org. Chem., 39, 1437 (1974)].
Amino alcohols constitute an important class of organic compounds, many of which are extremely useful synthetic intermediates for the preparation of specialty organic chemicals, pharmaceuticals, and agricultural products. Also, the amino alcohols derived from naturally occurring .alpha.-amino acids have been found to be potent, reversible inhibitors of protein synthesis [R. Calendar and P. Berg, Biochemistry, 5, 1690 (1966); D. Cassio, et al., Biochemistry, 6, 827 (1967); P. Rouget and F. Chapeville, European J. Biochem., 4, 305 (1968); B. S. Hansen, et al., J. Biol. Chem., 247, 3854 (1972)]. Consequently, amino alcohols are important and useful chemicals, which presumably should be readily obtainable via reduction of the corresponding amino acids.
Since borane is known to be an effective reagent for the reduction of carboxylic acids [Yoon and coworkers (supra)], it might also be expected that this reagent would be useful for the preparation of amino alcohols via reduction of amino acids. In fact, Yoon and coworkers (supra) have described in detail a procedure for the reduction of p-aminobenzoic acid with borane-tetrahydrofuran and have even suggested this as a general procedure for the reduction of amino acids. Their procedure involves first dissolving the p-aminobenzoic acid in tetrahydrofuran, then treating the resulting solution with borane-tetrahydrofuran. This may indeed be a general procedure for the reduction of those amino acids which have some solubility in tetrahydrofuran but, in general, most amino acids are almost completely insoluble in ether solvents due to zwitterion formation. ##EQU1##
I have found that all of the following amino acids are insoluble in tetrahydrofuran: m-aminobenzoic acid, p-dimethylaminobenzoic acids, leucine, valine, serine, tyrosine, methioniine, alanine, histidine, lysine, glutamic acid, aspartic acid, and 6-aminocaproic acid. The addition of borane-tetrahydrofuran to the above amino acids in slurries at 20.degree.-25.degree.C results in only an extremely slow evolution of hydrogen and the amino acid does not dissolve, indicating that essentially no reduction has occurred. Repeating the above procedure using borane-dimethyl sulfide in place of borane-tetrahydrofuran gives essentially the same result. Also, when this borane-dimethyl sulfide/amino acid/tetrahydofuran slurry is heated to, and maintained at, reflux an increased rate of hydrogen evolution is observed and, in many cases, the amino acid slowly dissolves, indicating an apparent slow rate of reduction.
It has been reported that phenylalaninol (2-amino-3-phenyl-1-propanol) was prepared by reducing phenylalanine with diborane [A. V. Emes and L. C, Vinings, Canadian J. Biochem., 48, 613 (1970)]. However, the experimental details, purity of the product, and yield were not reported. A series of substituted phenylalanines were also recently reported to be reduced by diborane in anhydrous tetrahydrofuran giving good yields of the corresponding substituted phenylalaninols [M. L. Anhoury, et al., J. Chem. Soc. Perkin Transactions I, 191 (1974)]. In both of these cases the starting amino acids must be at least slightly soluble in the tetrahydrofuran.
In addition to the low reactivity of most amino acids due to their insolubility in the common ether solvents used for active hydride reductions, another serious disadvantage is the necessity of using a large excess of the borane reagent to compensate for the active hydrogens on the amino group and for the formation of an unreactive borane-amine complex. Thus, for the reduction of one molar equivalent of an amino acid, one molar equivalent of BH.sub.3 is required to reduce the carboxylic acid group, two-thirds of a molar equivalent of BH.sub.3 is required for the two active hydrogens on the amino group, and another molar equivalent of BH.sub.3 is required for the formation of a borane-amine complex. This means that a total of 22/3 molar equivalents of BH.sub.3 are required to reduce only one molar equivalent of an amino acid, with 12/3 molar equivalents of BH.sub.3 being completely wasted and only one molar equivalent being used for the desired reduction process.
On a small laboratory scale where the value of the amino acid is quite high compared to the cost of the borane reagent, this need for excess borane reagent to accomplish the desired reduction is of small consequence. However, on a commercial scale this added cost of the required extra borane reagent can become quite important. The cost of the excess reagent may, in many cases, be all that is necessary to make the reduction process economiclly unattractive for the production of amino alcohols.
The limitations observed in the direct borane reduction of amino acids due to the insolubility of most amino acids in the ether solvents used for borane reductions and the disadvantage of having to use a large excess of borane reagent to achieve complete reduction of the carboxylic acid group have now been overcome by the use of the present invention.